The present invention relates to novel natural product derivatives, to processes for their preparation, to pharmaceutical compositions comprising them and to their use in the treatment of disorders in humans or animals.
EP-A-0339596 discloses antibiotics of the formula 
which are obtained by cultivating a microorganism of the genus Flexibacter.
Specifically, this publication also describes the following compounds 
in which the carbon atom A has the S configuration (TAN-1057A) or the R configuration (TAN-1057B). Y. Funabashi et al.; Tetrahedron 49, 13, 1993 describe the chemical and structural characterization of TAN-1057A and TAN-1057. B. N. Katayama et al.; J. Antibiotics, 46, 606, 1993 report about the taxonomy of TAN-1057-producing organisms and the biological properties of TAN-1057. Total syntheses of TAN-1057 compounds were published by C. Yuan and R. M. Williams in J. Am. Chem. Soc.; 119, 11777, 1997 and A. de Meijere et al. in Eur. J. Org. Chem. 1998, 777. First derivatives of TAN-1057 compounds were described by R. M. Williams in J. Antibiotics; 51, 189, 1998. However, most of the derivatizations relate to the cyclic amidinourea moiety of the molecule. Thus, for example, derivatives of the type 
in which R represents Ac, COPh, COOMe, SO2Me and CO2CH2Ph are described.
WO 99/07685, which was published after the date of priority of the present application, discloses derivatives, acylated at the cyclic amidinourea moiety of the molecule and additionally phosphorylated, of the general formula: 
in which R2 represents 
Only two derivatizations (J. Antibiotics; 51, 189, 1998) relate to the (S)-xcex2-homoarginine moiety: 
However, these derivatizations resulted in a complete loss of biological activity.
It was the object of the inventors of the present invention to synthesize further derivatives of the TAN-1057 compounds to investigate their biological and/or pharmacological actions. After overcoming difficult synthetic problems, the inventors succeeded in synthesizing further novel compounds which are derivatized in the (S)-xcex2-homoarginine moiety of TAN 1057, using a novel, generally applicable process, which compounds, surprisingly, have considerably lower toxicity, with comparable activity.
Accordingly, the present invention provides compounds of the general formula: 
in which
R1 represents hydrogen or (C1-C6)alkyl,
X represents a group of the formula xe2x80x94(CH2)mxe2x80x94, in which m is 0, 1 or 2,
D is selected from groups of the formulae D1 to D3
xe2x80x83in which R2 represents hydrogen or hydroxyl,
R3 represents hydrogen, or
R2 and R3 together form an oxo group,
Y represents a straight-chain or branched (C1-C5)alkanediyl group in which optionally one carbon atom may be replaced by xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and which may optionally be substituted by hydroxyl or oxo, or represents a group of the formulae below 
xe2x80x83in which r and s are identical or different and are 0, 1 or 2,
Z represents a group selected from groups of the formulae 
xe2x80x83in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 and R19 in each case independently of one another are selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C4)alkanoyl, t-butoxycarbonyl, benzyloxycarbonyl and benzyl,
Q represents oxygen or sulphur and
pis 1, 2 or 3 and
Het represents a 5- or 6-membered heteroaromatic group having 1 to 4 nitrogen atoms,
except for compounds in which
R1 represents methyl, m is 1, D represents D1, Y represents xe2x80x94(CH2)3xe2x80x94 and Z represents a group of the formula 
xe2x80x83and pharmaceutically acceptable salts thereof.
The case corresponding to TAN 1057A/B, in which R1 represents methyl, m is 1, D represents D1, Y represents xe2x80x94(CH2)3xe2x80x94 and Z represents a group of the formula 
which is excluded from the compounds claimed according to the invention, corresponds to the case in which D represents D2, R2 and R3 represent hydrogen, R represents methyl, m is 1, Y represents xe2x80x94(CH2)2xe2x80x94 and Z represents a group of the formula 
which, as a consequence, is likewise excluded from the compounds according to the invention.
The present invention preferably provides compounds of the general formula: 
in which R1 represents hydrogen or (C1-C6)alkyl,
X represents a group of the formula xe2x80x94(CH2)mxe2x80x94, in which m is 0, 1 or 2,
D is selected from groups of the formulae D1 to D3
xe2x80x83in which R2 represents hydrogen or hydroxyl,
R3 represents hydrogen, or
R2 and R3 together form an oxo group,
Y represents a straight-chain or branched (C1-C5)alkanediyl group in which optionally one carbon atom may be replaced by xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and which may optionally be substituted by hydroxyl or oxo, or represents a group of the formulae below 
xe2x80x83in which r and s are identical or different and are 0, 1 or 2,
Z represents a group selected from groups of the formulae 
xe2x80x83in which R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 and R19 in each case independently of one another are selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C4)alkanoyl, t-butoxycarbonyl, benzyloxycarbonyl and benzyl,
Q represents oxygen or sulphur and
p is 1, 2 or 3 and
Het represents a 5- or 6-membered heteroaromatic group having 1 to 4 nitrogen atoms,
except for compounds in which
R1 represents methyl, m is 1, D represents D1, Y represents xe2x80x94(CH2)3xe2x80x94 and Z represents a group of the formula 
xe2x80x83(corresponds to the case in which D represents D2, R2 and R3 represent hydrogen, R1 represents methyl, m is 1, Y represents xe2x80x94(CH2)2xe2x80x94 and Z represents a group of the formula 
xe2x80x83and pharmaceutically acceptable salts thereof.
m in the group of the formula xe2x80x94(CH2)mxe2x80x94 for X is preferably 1 or 2. Accordingly, the group of the formula xe2x80x94(CH2)mxe2x80x94 for X preferably includes a methylene or an ethylene (ethane-1,2-diyl) group. X is particularly preferably a methylene group.
A straight-chain or branched (C1-C5)alkanediyl group in which optionally one carbon atom may be replaced by xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and which, additionally, may optionally be substituted by hydroxyl or oxo, in the definition of Y includes, for example, straight-chain (C1-C5)alkanediyl groups, such as methylene, ethylene, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl. Preference is given to straight-chain (C1-C4)alkanediyl groups.
A straight-chain or branched (C1-C5)alkanediyl group in which one carbon atom is replaced by xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and which, additionally, may optionally be substituted by hydroxyl or oxo, in the definition of Y includes, for example, groups of the formulae: 
Here, either side of the groups may be attached to Z.
The groups of the formulae 
for Y include, for example, symmetrical radicals in which r and s are identical, or asymmetrical radicals; symmetrical radicals in which r and s are 0, i.e. 1,2-phenylene, 1,3-phenylene and 1,4-phenylene, being preferred. Particular preference is given to 1,3- or m-phenylene.
In the general formula (I), Z is selected from groups of the formulae 
in which R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 and R19 in each case independently of one another are selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C4)alkanoyl, t-butoxycarbonyl, benzyloxycarbonyl and benzyl,
Q represents oxygen or sulphur and
p is 1, 2, or 3 and
Het represents a 5- or 6-membered heteroaromatic group having 1 to 4 nitrogen atoms.
Among these groups for Z 
R4, R5, R6, R7 and R17 are as defined above are preferred.
Z is particularly preferably a group of the formula 
in which R4, R5, R6 and R7 are as defined above, preferably hydrogen.
In the group of the formula 
for Z, Het is advantageously selected from the group consisting of the group of the formulae: 
Here, the azoles, i.e. the five-membered unsaturated heterocyclic ring systems having 1 to 4 nitrogen atoms, can be attached either via a carbon or via a nitrogen atom.
Among these radicals, six-membered heteroaromatics having 1 to 3 nitrogen atoms are preferred.
Particularly preferably, Het represents pyridyl, including 2-pyridyl, 3-pyridyl and 4-pyridyl, 2-pyridyl being particularly preferred.
Very particularly preferably, Z represents 
In a further preferred embodiment, Z represents a group of the formula 
in which R18 and R19 are as defined above.
(C1-C6)Alkyl in the above definitions of R1 and R4 to R19 represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl, iso-butyl, pentyl and hexyl, preference being given to (C1-C4)alkyl groups and particular preference being given to methyl.
R4 to R19 preferably represent hydrogen.
(C1-C4)Alkanoyl in the definition of R4 to R19 represents, for example, formyl, acetyl, propionyl and butanoyl, preference being given to formyl and acetyl.
Q preferably represents oxygen.
p is preferably 1 or 2.
In a preferred embodiment of the invention, the group D represents 
In a further preferred embodiment of the invention, the group D represents 
in which R2 and R3 are as defined above and are preferably hydrogen.
In a preferred embodiment of the invention, the group D represents 
Among these, preference is given to the groups D1 and D2 and particular preference is given to D1. Preference is furthermore given to the case in which both R1 and R2 in D2 are hydrogen.
Suitable pharmaceutically acceptable salts of the compounds of the general formula (I) can be conventional non-toxic salts including, for example, salts with mineral acids, carboxylic acids or sulphonic acids. Such acid addition salts include organic acid salts (for example acetates, propionates, lactates, citrates, benzoates, trifluoroacetates, maleates, tartrates, fumarates, methanesulphonates, ethanesulphonates, benzenesulphonates, formates, toluenesulphonates, naphthalene-disulphonates, etc.) and inorganic acid salts (for example hydrochlorides, hydrobromides, hydrolodides, sulphates, nitrates, phosphates, etc.).
As a consequence of double bonds and asymmetric carbon atoms, the compounds of the general formula (I) can be present as stereoisomers, such as cis/trans isomers and configuration isomers, such as enantiomers or diastereomers; these isomers and mixtures thereof are included in the scope of the present invention.
The compounds according to the invention are prepared by reacting compounds of the formula (II) 
in which X, Y and Z are as defined above and Dxe2x80x2 is selected from groups of the formulae Dxe2x80x21 to Dxe2x80x23
in which R2 and R3 are as defined above and A is a conventionally protected amino group, with compounds of the formula (III) 
in which R1 is as defined above, in the presence of coupling agents, if desired in the presence of bases, and the conventional protective group in the protected amino group A is removed by methods known per se.
The compound of the formula (III) is synthesized using the method of V. V. Sokolov, S. I. Kozhushkov, S. Nikolskaya, V. N. Belov, M. Es-Sayed, A. de Meijere, Eur. J. Org. Chem. 1998, 777.
Compounds of the formula (II) used for the amide formation are appropriately protected amino acids which can be obtained, for example, by chain extension from the xcex1-amino acids (cf. H. M. M. Bastiaans, A. E. Alewijnse, J. L. van der Baan, H. C. J. Ottenheijm, Tetrahedron Lett. 1994, 35, 7659).
If the straight-chain or branched (C1-C5)alkanediyl group for Y contains functional groups, such as hydroxyl, keto, ester or amide functions, their introduction or synthesis is carried out by standard methods (see, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry], Volume XV/1 and 2.).
3-(Benzyloxycarbonylamino)-3-[3xe2x80x2-(N-benzyloxycarbonylguanidino)phenyl]-propionic acid, for example, is prepared according to Scheme 1 below. 
Here, compound D (E. Proft, F.-J. Becker, J. prakt Chemie 1965, 30, 18), for example, is esterified with methanol in the presence of, for example, concentrated sulphuric acid. In the two-phase system dichloromethane/base, such as, for example, saturated aqueous sodium bicarbonate solution, the free amino group is converted into the benzyl carbamate using benzyl chloroformate. The aromatic nitro group is reduced using tin(II) chloride. Subsequent reaction with bis(benzyloxycarbonyl) S-methylthiourea (W. Su, Synth. Commun. 1996, 26, 407) in the presence of mercury(II) chloride and basic hydrolysis of the methyl ester gives the carboxylic acid I.
In the above reactions, it is also possible to use the generally employable solvents, acids and bases listed below in place of those mentioned here.